ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.1111T>C (p.Ser371Pro) (rs61752371)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000132846 SCV000247926 likely benign not specified 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000132846 SCV000513569 benign not specified 2015-08-14 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000470986 SCV000556753 likely benign Severe neonatal-onset encephalopathy with microcephaly 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000132846 SCV000919620 likely benign not specified 2017-12-05 criteria provided, single submitter clinical testing Variant summary: The MECP2 c.1075T>C (p.Ser359Pro) variant involves the alteration of a non-conserved nucleotide, changing a small, polar amino acid (S) to a medium, hydrophobic residue (P). 2/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). S359 has been shown to be phosphorylated in human skin fibroblasts, and phosphorylation of MECP2 has been shown to modulate its binding affinity, gene expression, and cellular adaptations to stimuli and neuronal plasticity (Bellini_2014). However, the functional impact of replacing S359 with a proline residue has not been studied. S359 is located within the C-terminal domain, whereas most classic RTT-causing mutations lie within the methyl-CpG-binding (MBD) or transcriptional-repression (TRD) functional domains (Bienvenu_ 2002). This variant was found in 17/198183 control chromosomes at a frequency of 0.0000858, which is approximately 10 times the estimated maximal expected allele frequency of a pathogenic MECP2 variant (0.0000083), suggesting this variant is likely a benign polymorphism. This variant has been cited in both patients and controls. A family co-segregation study showed that the variant was found in the healthy mother, healthy maternal aunt, and 3 healthy cousins (1 male and 2 females) of an intellectually disabled male (Moncla_2002), suggesting that S359P is not a pathogenic variant regardless of its potential functional impact. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as likely benign.
RettBASE RCV000132846 SCV000187825 benign not specified 2008-01-21 no assertion criteria provided curation

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